The proposed research would be directed at elucidating the role of insulin disposition in insulin homeostasis and possible derangements in diabetes mellitus. The these ends the effect of factors reported to decrease hepatic degradation of insulin, such as starvation and alloxan- diabetes, on the plasma clearance, tissue distribution and degradation of I131 labeled insulin and related peptides would be investigated in the rat. Also, the kinetics, nature, sites and specificity of the degradative and transport processes for I131-insulin and related peptides and the relationships between plasma membrane binding, biological activity and degradation would be investigated in subcellular fraction of rat liver both in vitro and in vivo following intraportal injection of the hormones. The studies would be extended to biopsy specimens of liver of selected non-diabetic human subjects. The physiological data would be also utilized to develop comprehensive mathematical models which would predict observed data and account for the physiological processes known or believed to occur. Such models would ultimately be utilized to analyze curves of I131-insulin and related peptide disappearance in plasma of non-diabetic and diabetic subjects to determine the specific causes that produce and influence the magnitudes and rates of change in plasma insulin levels following glucose administration in terms of dynamics, reaction rates and turnover. Studies would also be carried out on the chromatographic behavior in sephadex gel of immunoreactive insulin in plasma following oral glucose loads to normal and maturity-onset diabetic subjects in view of preliminary data suggesting the secretion of a component different from the standard insulin monomer.